Prefrontal cortex (PFC), a key region for many executive processes, such as working memory, attention and emotional control, is implicated in stress-related disorders including depression, anxiety and posttraumatic stress disorder. The function of PFC is strongly influenced by corticosterone, the major stress hormone released from adrenal cortex in response to stressful events, but the underlying mechanisms are elusive. Our long-term goal is to delineate the mechanisms by which stress affects PFC synaptic functions. We propose that NMDARs and AMPARs are potential targets of stress hormones in PFC that are critically involved in the regulation of cognitive and emotional processes. To test this, we will address the following three specific aims: (1) To study the changes in glutamatergic transmission induced by stress in PFC neurons. Our preliminary results show that in vivo acute stress or in vitro short-term corticosterone treatment causes a delayed and long- lasting potentiation of NMDAR- and AMPAR-mediated synaptic transmission and ionic currents in PFC pyramidal neurons. We will investigate the impact of different acute stressors on PFC synaptic functions and the stress hormone receptors involved. The impact of in vivo chronic stress or in vitro long-term corticosterone treatment on PFC glutamatergic responses will also be examined and compared. (2) To study the molecular mechanisms for acute stress-induced changes in PFC synaptic functions. We will investigate the role of several key signaling molecules, including the serum- and glucocorticoid-inducible kinase (SGK) and Rab family small GTPases that function as specific regulators of vesicle trafficking at different stages of endocytosis/exocytosis. (3) To study the stress-induced changes in glutamate receptor trafficking and expression in PFC neurons. We will investigate whether the acute stress-induced increase in glutamatergic synaptic transmission is associated with the increased delivery of NMDARs and AMPARs to the neuronal surface in stressed animals. The impact of chronic stress on glutamate receptor expression and trafficking will also be examined. To understand the broader significance and clinical relevance of the stress-induced synaptic changes in PFC, we will perform behavioral studies to examine the impact of stress on working memory, a key cognitive function relying on glutamatergic transmission in PFC. Using combined electrophysiological, biochemical, morphological, molecular and behavioral approaches, the proposal will address important issues on the functions of stress hormones, particularly corticosteroids, in PFC neurons. Knowledge gained from this study would shed light on how the glucocorticoid receptor and the glutamate system are mechanistically linked, how their interactions may be critical for maintaining normal cognition and emotion, and how the aberrant corticosteroid-glutamate interactions may contribute to the pathophysiology of mental illnesses.